Colorectal cancer is the second most common cause of cancer-related death in the United States. Twin studies suggest that 35% of all colorectal cancer cases are inherited. High-penetrance tumor susceptibility genes account for at most 3-6% of all colorectal cancer cases and the remainder of the unexplained risk is likely due to a combination of low to moderate penetrance genes. Recent genome-wide association studies have identified several SNPs near genes belonging to the transforming growth factor beta (TGF-beta) superfamily such as GREM1 and SMAD7. Together with the recent discovery that constitutively decreased TGFBR1 expression is a potent modifier of colorectal cancer risk, these findings strongly suggest that germline variants of the TGF-beta superfamily may account for a sizeable proportion of colorectal cancer cases. The TGF-beta superfamily signaling pathways mediate many different biological processes during embryonic development, and in adult organisms they play a role in tissue homeostasis. TGF-beta has a central role in inhibiting cell proliferation and also modulates processes such as cell invasion, immune regulation, and microenvironment modification. Mutations in the TGF-beta type II receptor (TGFBR2) are estimated to occur in approximately 30% of colorectal carcinomas. Mutations in SMAD4 and BMPR1A are found in patients with familial juvenile polyposis, an autosomal dominant condition associated with an increased risk of colorectal cancer. This chapter provides an overview of the genetic basis of colorectal cancer and discusses recent discoveries related to alterations in the TGF-beta pathways and their role in the development of colorectal cancer.